Based on our analysis of severe blunt trauma patients enrolled in the Inflammation and the Host Response to Injury Program, our investigators propose that a large proportion of patients who would generally meet the inclusion criteria for a study of severely injured patients are not in need of immunomodulatory therapy and are unlikely to benefit from such therapies (IFN?, -glucan or immunoglobulin). In contrast, there exists a subset of patients who will have a protracted clinical course, and would benefit from interventional therapies with biological-response modifiers. Inclusion of the former patients in such a clinical trial who would either not benefit or might be harmed by such therapies has made it extremely difficult to identify the beneficial effects of these interventions in the latter subset of patients who would be responsive to these therapies. We believe that this failure to identify those patients a priori who may actually benefit from intervention (personalized therapies) is one reason that clinical trials in trauma and sepsis have failed. Therefore, it is absolutely essential that a rapid prognostic be developed and used to prospectively identify those severely injured patients who would be good candidates for the immunomodulatory intervention. The overall goal of the proposed clinical trial would be to determine whether administration of IFN? will alter the clinical trajectory in a subgroup of severely injured patient identified by a prognostic indicator based on a genomic signature likely to have an adverse clinical outcome and who would benefit from such therapies. Blood samples will be collected with the goal being to determine whether rh-IFN? treatment restores an improved genomic signature associated with better outcomes. A primary clinical goal is to determine whether rh-IFN? reduces time to recovery and increases organ-failure free days in this at-risk population. PUBLIC HEALTH RELEVANCE: We propose to organize a clinical trial to determine whether administration of interferon- will alter the clinical trajectory in a subgroup of severely injured patients, identified by a prognostic indicator based in part on the leukocyte genomic response to trauma as being likely to have an adverse clinical outcome and benefit from such therapies. Our overarching hypothesis is that changes in the blood leukocyte genome can be used to predict distant clinical outcomes and to detect response to therapies in patients, not only with severe trauma and critical illness. A primary objective is to determine whether rhIFN-? reduces time to recovery and increases organ-failure free days in the subgroup of patients identified by the prognostic test to be at increased risk.